The novel Isatin analog KS99 targets stemness markers in acute myeloid leukemia
Charyguly Annageldiyev,
Krishne Gowda,
Trupti Patel,
Priyanjali Bhattacharya,
Su-Fern Tan,
Soumya Iyer,
Dhimant Desai,
Sinisa Dovat,
David J. Feith,
Thomas P. Loughran,
Shantu Amin,
David Claxton,
Arati Sharma
Affiliations
Charyguly Annageldiyev
Department of Medicine, Division of Hematology and Oncology, Pennsylvania State University College of Medicine, Hershey, PA, USA;Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA, USA
Krishne Gowda
Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA, USA;Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA
Trupti Patel
Department of Integrative Biotechnology, SBST, VIT Vellore, Tamilnadu, India
Priyanjali Bhattacharya
Department of Integrative Biotechnology, SBST, VIT Vellore, Tamilnadu, India
Su-Fern Tan
Department of Medicine, Division of Hematology and Oncology, University of Virginia School of Medicine, Charlottesville, VA, USA
Soumya Iyer
Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, USA
Dhimant Desai
Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA, USA;Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA
Sinisa Dovat
Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, USA
David J. Feith
Department of Medicine, Division of Hematology and Oncology, University of Virginia School of Medicine, Charlottesville, VA, USA;University of Virginia Cancer Center, Charlottesville, VA, USA
Thomas P. Loughran
Department of Medicine, Division of Hematology and Oncology, University of Virginia School of Medicine, Charlottesville, VA, USA;University of Virginia Cancer Center, Charlottesville, VA, USA
Shantu Amin
Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA, USA;Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA
David Claxton
Department of Medicine, Division of Hematology and Oncology, Pennsylvania State University College of Medicine, Hershey, PA, USA;Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA, USA
Arati Sharma
Department of Medicine, Division of Hematology and Oncology, Pennsylvania State University College of Medicine, Hershey, PA, USA;Penn State Hershey Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA, USA;Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA
Leukemic stem cells are multipotent, self-renewing, highly proliferative cells that can withstand drug treatments. Although currently available treatments potentially destroy blast cells, they fail to eradicate leukemic progenitor cells completely. Aldehyde dehydrogenase and STAT3 are frequently up-regulated in pre-leukemic stem cells as well as in acute myeloid leukemia (AML) expressing the CD34+CD38− phenotype. The Isatin analog, KS99 has shown anticancer activity against multiple myeloma which may, in part, be mediated by inhibition of Bruton’s tyrosine kinase activation. Here we demonstrate that KS99 selectively targets leukemic stem cells with high aldehyde dehydrogenase activity and inhibits phosphorylation of STAT3. KS99 targeted cells co-expressing CD34, CD38, CD123, TIM-3, or CD96 immunophenotypes in AML, alone or in combination with the standard therapeutic agent cytarabine. AML with myelodysplastic-related changes was more sensitive than de novo AML with or without NPM1 mutation. KS99 treatment reduced the clonogenicity of primary human AML cells as compared to normal cord blood mononuclear cells. Downregulation of phosphorylated Bruton’s tyrosine kinase, STAT3, and aldehyde dehydrogenase was observed, suggesting interaction with KS99 as predicted through docking. KS99 with or without cytarabine showed in vivo preclinical efficacy in human and mouse AML animal models and prolonged survival. KS99 was well tolerated with overall negligible adverse effects. In conclusion, KS99 inhibits aldehyde dehydrogenase and STAT3 activities and causes cell death of leukemic stem cells, but not normal hematopoietic stem and progenitor cells.
